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Therapy

Lyudmila Bravinskaya , cosmetologist-methodologist, Odessa Medical University (Odessa)<hr /> <a href="https://www.instagram.com/cosmetology.pro.bhub/?hl=ru" style="text-align: center;" target="_blank"><img alt="" src="https://pro.bhub.com.ua/cosmetology/upload/files/%D0%A1%D0%90%D0%99%D0%A2/BANER_PROCosm-insta.gif" style="width: 1200px; height: 100px;" /></a> The term &quot;apoptosis&quot; is made up of two Greek words and literally means &quot;falling off of leaves.&quot; Cells that have completed their development cycle - aging, damaged, mutant, infected - undergo apoptosis. In multicellular organisms, apoptosis is involved in the processes of differentiation and morphogenesis, as well as in maintaining cellular homeostasis, and in the formation and functioning of the immune system. Currently, the basic mechanisms of apoptosis in cells have been established. But active research continues on the regulators and activators of apoptosis to establish a more accurate picture of this process. Scientists&#39; interest is related to the possibility of applying knowledge about programmed cell death in medicine in the treatment of cancer, autoimmune and neurodegenerative diseases.<table border="1" cellpadding="1" cellspacing="1"><tbody><tr><td> There are many definitions of the concept “apoptosis”. In some sources, apoptosis refers to the phenomenon of programmed cell death, accompanied by a set of characteristic cytological signs (markers of apoptosis) and molecular processes that differ in unicellular and multicellular organisms (that is, changes in the structure and functioning of the cell characteristic of apoptosis). Other sources describe apoptosis as a form of cell death, manifested in a decrease in its size, condensation (compaction) and fragmentation of chromatin, compaction of the outer and cytoplasmic membranes without the release of cell contents into the environment.</td></tr></tbody></table> Mechanisms of apoptosis How is the apoptosis program activated in a cell? We can conditionally divide the factors and their triggers into two groups:<ul><li> mitochondrial mechanism;</li><li> receptor mechanism.</li></ul><h2> Mitochondrial mechanism</h2> Occurs when the cell condition is unsatisfactory, which can be caused by various types of radiation, temperature changes, the action of chemicals, toxins, stressful situations, malnutrition of the cell and lack of oxygen in the tissues. Despite the variety of reasons for the triggering of apoptosis, the mechanism of its implementation is the same. It is associated with damage to the mitochondrial membrane, which leads to the release of cytochromes into the cytoplasm (respiratory enzymes firmly associated with mitochondrial membranes, carrying out the transfer of electrons and hydrogen in the cell from oxidized organic substances to molecular oxygen, thereby forming an energy-rich compound - ATP). Cytochrome, together with the cytoplasmic factor APAF-1 (Apoptose protease activation factor), inactive caspase and ATP make up the apoptosomal complex. The APAF-1 factor activates caspases (special proteolytic enzymes, which are cysteine proteases and are represented in the cell by multiple variants). It is assumed that these enzymes form a proteolytic cascade, mutually activating each other and thereby leading to cell degradation. Mitochondrial proteins of the Bcl-2 family are also involved in the implementation of these processes.<h2> Receptor mechanism</h2> The cell receives a signal to begin the process of apoptosis when special receptors located on its surface are activated. In this case, the cell is quite viable, but from the standpoint of the whole organism, a signal is sent to it about “self-destruction”. The receptor detects the presence of intercellular signals and, in response to this, quickly triggers the intracellular mechanism of apoptosis, combining into a special group - death receptors, which differ from other receptors by the presence in the cytoplasmic part of the cell of a special “death domain”, necessary to turn on the signal leading to apoptosis. Among these receptors, the best known is the Fas receptor, the ligand of which is a trimeric molecule belonging to the tumor necrosis factor (TNF) family.<h2> Other apoptosis activators</h2> Various metabolites and hormones can also activate apoptosis: anti-inflammatory cytokines, steroid hormones, nitric oxide and free radicals. All these factors, in turn, cause excessive damage to chromosomes, numerous DNA breaks, and disturbances in their conformation. The trigger point can also be damage to intracellular membranes and lipid peroxidation. For a deeper understanding of the mechanisms of regulation, it is necessary to mention some influences and factors that play an important role in the development of apoptosis. In the 90s of the twentieth century, a number of genes involved in the regulation of apoptosis were discovered. One of them encodes the p53 protein, which is an activator of apoptosis. An increase in the level of the p53 protein occurs in response to DNA damage, and induces apoptosis by various mechanisms: influence on the cell cycle, stimulation of the expression of the Fas receptor, effects on neighboring cells, etc. The action of the p53 protein increases the time of DNA repair, which protects the body from the spread cells with dangerous mutations. It is important to emphasize that p53-dependent apoptosis eliminates from the body not only damaged cells, but also cells in which unregulated stimulation of proliferation processes is observed. A cell undergoes apoptosis if DNA damage occurs in the nucleus that cannot be corrected by the repair system. This process is monitored by a protein encoded by the p53 gene.<h2> Apoptosis and necrosis Damage to cellular structures leading to apoptosis should not be excessive, otherwise the process of cell death becomes uncontrollable and represents another form of cell death - necrosis.</h2> Necrosis is a pathological process that starts in response to any external or internal damage (infection, chemical exposure, radiation, insufficient blood supply, etc.). Necrosis manifests itself in swelling, denaturation and coagulation of cytoplasmic proteins, destruction of cellular organelles and, finally, the entire cell. The basis of necrosis is a violation of the integrity of the membrane, which ensures the isolation of the cell from the external environment. Lysosomal enzymes are released from the lysosomes, which digest the contents of the cell, the cell swells, the membrane ruptures with the destruction of subcellular structures due to osmotic shock, and the DNA undergoes uncontrolled fragmentation. The cell contents are released into the extracellular environment, where they are absorbed by phagocytes, which leads to the development of an inflammatory reaction in the surrounding tissues. During apoptosis, on the contrary, the cell size decreases, the membrane thickens, swellings are formed, resulting in the formation of cell fragments containing fragments of nuclei (apoptotic bodies). Contacts with neighboring cells are weakened, DNA undergoes strictly ordered fragmentation, since its threads are broken only between nucleosomes (the structures in which DNA is packaged). During apoptosis, the integrity of the membranes is preserved, the organelles look morphologically intact, and the products of cell fragmentation, apoptotic bodies, are separate fragments surrounded by a membrane. Thus, the fate of cells undergoing apoptosis and necrosis is different. The necrotic cell bursts and its contents end up in the intercellular space, causing damage to neighboring cells and initiating inflammation. Apoptotic cells remain impenetrable and are very quickly absorbed by phagocytes. This is explained by the fact that a number of molecules (glycoproteins, phosphatidylserine, etc.) appear on the cell surface during the process of apoptosis, recognized by phagocytes and serving as a signal for phagocytosis. The main differences between apoptosis and necrosis are reflected in Table 1. Table 1. Main differences between apoptosis and necrosis<table border="1" cellpadding="1" cellspacing="1"><tbody><tr><td> Index</td><td> Apoptosis</td><td> Necrosis</td></tr><tr><td> Trigger factor</td><td> Increased permeability of mitochondrial membranes or a signal perceived by membrane receptors</td><td> Inadequate environmental conditions, toxic agents</td></tr><tr><td> Development speed</td><td> 1 – 4 hours</td><td> Less than an hour</td></tr><tr><td> Causes of cell death</td><td> Violation of cell energy, DNA degradation</td><td> Violation of membrane integrity, osmotic processes</td></tr><tr><td> Changing cell size</td><td> Reduction (wrinkling)</td><td> Increase (swelling)</td></tr><tr><td> Kernel change</td><td> Chromatin condensation, fragmentation</td><td> Swelling</td></tr><tr><td> Change in cytoplasm</td><td> Condensation of the cytoplasm, compaction of granules</td><td> Lysis of granules</td></tr><tr><td> Cell membrane change</td><td> Loss of microvilli, formation of swellings and compactions</td><td> Integrity violation</td></tr><tr><td> DNA state</td><td> Ordered (internucleosomal) degradation</td><td> Disordered degradation</td></tr><tr><td> Energy dependence</td><td> Depends</td><td> Does not depend</td></tr></tbody></table><h2> Stages of apoptosis</h2> The mechanisms of apoptosis are complex and diverse. They represent a complex molecular cascade, which is being studied by many laboratories around the world. The undoubted importance of these studies in the aspect of oncology and gerontology is proven by the success of cancer therapy with inducers of cancer cell apoptosis. There are three stages in the development of apoptosis:<ul><li> signal (inductor);</li><li> effector;</li><li> degradation (destruction).</li></ul> The cell receives a signal that its death is necessary for the further functioning of the body. Inducers of apoptosis can be both external (extracellular) factors and intracellular signals. The signal is perceived by the receptor and is then sequentially transmitted to intermediary molecules (messengers) of various orders and reaches the nucleus, where the cellular “suicide” program is activated. The first morphological signs of apoptosis are recorded in the nucleus - condensation of chromatin with the formation of its osmiophilic accumulations adjacent to the nuclear membrane. Later, invaginations (depressions) of the nuclear membrane appear, and fragmentation of the nucleus occurs. The basis of chromatin degradation is the enzymatic cleavage of DNA. First, fragments are formed that include 700, 250, 70 thousand base pairs. Then - fragments containing 30–50 thousand base pairs. After the implementation of this stage, the process becomes irreversible. Then comes internucleosomal DNA disintegration, that is, breaks in the DNA strands located between nucleosomes. The separated nuclear fragments bounded by the membrane are called apoptotic bodies. In the cytoplasm, expansion of the endoplasmic reticulum, condensation and wrinkling of granules occurs. The most important sign of apoptosis is a decrease in the transmembrane potential of mitochondria and the release of various apoptogenic factors (cytochrome, procaspases, apoptosis-inducing factor) into the cytoplasm. It is the disruption of the barrier function of mitochondrial membranes that plays a key role in the development of many types of apoptosis. The cell membrane loses its villousness and forms bubble-like swellings. The cells are rounded and separated from the substrate. Various molecules recognized by phagocytes are expressed on the cell surface, resulting in the engulfment of the cell body by other cells and its degradation surrounded by lysosomes of phagocytic cells.<table border="1" cellpadding="1" cellspacing="1"><tbody><tr><td> The role of apoptosis in the physiological processes of the body<ul><li> Removal of genetically defective, pre-tumor cells</li><li> Role in embryogenesis (destruction of various tissue primordia and organ formation)</li><li> Participation in the immune system (destruction of autoreactive clones of T-lymphocytes, etc.)</li><li> Participation in the female reproductive system (death of follicular cells, etc.)</li><li> Elimination of damaged and aging cells – fibroblasts, hepatocytes</li><li> Elimination of postmitotic cells - neurons, cardiomyocytes</li><li> Preservation of tissue homeostasis – maintaining a constant number of cells</li><li> Effect on the development of degenerative or neoplastic age-related changes</li><li> Implementation of some effector functions of immunity</li></ul></td></tr></tbody></table><h2> The influence of apoptosis on the aging process</h2> Current knowledge shows that there is a relationship between dysregulation of apoptosis and a number of age-related pathologies and aging phenotypes. One of the hypotheses for explaining the molecular genetic mechanisms of aging of the body postulates: aging of the body is, in fact, aging and apoptosis of key cells, the death of which can affect the physiology of the entire organism. There is still debate about the role of apoptosis in the aging process, while some researchers are supporters of the theory of cellular apoptosis, holding the opinion that aging occurs as a result of the fact that more cells die in the body than are born, and dying functional cells are replaced by connective tissue. Based on this theory, old age is a disease that can and should be treated, and the body’s aging program can be disabled and thereby turn off the mechanism that shortens our life.<hr /> First published: Les Nouvelles Esthetiques Ukraine, No. 1 (71), 2012, pp. 76-78

Apoptosis is a program of aging of the body